This project is designed to deliver an anti-mucus drug for the treatment of respiratory airway disease. Airway diseases such as COPD and asthma are leading causes of morbidity and mortality in the U.S. and worldwide and serious forms of these diseases are linked to excess production of inflammatory mucus that obstructs the airway. However, there are no specific and effective therapies to attenuate airway mucus production. The cytokine IL-13 is implicated as a potent stimulus of airway mucus production in both asthma and COPD, and there are ongoing clinical trials of anti-IL-13 biologics. We reasoned that a small molecule to attenuate IL-13- stimulated (but not baseline) mucus production would address a major need for therapy of airway disease. Moreover, a drug targeted to airway epithelial cells themselves could offer significant advantages of specificity and efficacy. We discovered a novel pathway for mucus production that includes IL-13-induction of chloride channel calcium activated 1 (CLCA1) and then activation of mitogen activated protein kinase 13 (MAPK13). This CLCA1-MAPK13 signaling pathway was defined in experimental models but is also active in patients with excess mucus production due to COPD and likely asthma as well. Structure-based drug design led to the development of the first potent MAPK13 inhibitors, which safely attenuated IL-13-stimulated (but not baseline) mucus production in human airway epithelial cells and now appear effective in vitro and in vivo in a pig model of inflammatory airway mucus production. This Project therefore aims to deliver a safe and effective MAPK13 inhibitor for the treatment of excess mucus production found in COPD and related hypersecretory conditions. The UH2 Phase will accomplish two aims. Aim 1 will optimize lead MAPK13 inhibitors to attenuate IL-13- stimulated mucus production in human airway epithelial cells and will secure standardized in vitro ADMET evidence required for selection of a preclinical development candidate. Aim 2 will finalize conditions for IL-13- dependent airway mucus production in a large animal model that is suitable for testing anti-mucus drugs in vitro and in vivo. The UH3 Phase will advance three Aims. Aim 1 will formulate oral and inhaled candidate compounds and complete standardized in vivo ADMET-PK/PD studies. Aim 2 will proceed to safety and efficacy of candidate drugs in a large animal model of mucus production. Aim 3 will develop a protocol for use of candidate drug in humans, including safety, regulatory, and scale-up requirements for IND status. Each Aim has a defined timeline and benchmark. Together, we expect to arrive at a clinical candidate for a MAPK13 inhibitor as the first small-molecule therapeutic to control excess inflammatory mucus production. The projected market for our anti-mucus drug is hypersecretory conditions such as COPD and asthma. The Project will operate under a business plan that includes a patent filed by Washington University for proprietary anti-mucus compounds and eventual clinical trials in humans to achieve FDA approval of a MAPK13 inhibitor as an anti-mucus drug. (End of Abstract)